tbuckley/cabot-search huggingface dataset:
Biology and Targetability of the Extended Spectrum of<i>PIK3CA</i>Mutations Detected in Breast Carcinoma
Authors: Hope S. Rugo, Kira Raskina, Alexa B. Schrock, Russell W. Madison, Ryon P. Graf, Ethan S. Sokol, Smruthy Sivakumar, Jessica K. Lee, Virginia Fisher, Geoffrey R. Oxnard, Hanna Tukachinsky
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Alpelisib is a PI3K alpha (PI3Kα)-selective inhibitor approved for the treatment of hormone receptor–positive/HER2-negative (HR+/HER2−) PIK3CA-mutated advanced breast cancer (ABC) based on the SOLAR-1 trial, which defined 11 substitutions in exons 7, 9, and 20 in PIK3CA (SOLAR1m). We report alpelisib effectiveness for ABC harboring SOLAR1m, as well as other pathogenic PIK3CA mutations (OTHERm) using comprehensive genomic profiling (CGP). Experimental Design: A total of 33,977 tissue and 1,587 liquid biopsies were analyzed using hybrid capture–based CGP covering the entire coding sequence of PIK3CA. Clinical characteristics and treatment history were available for 10,750 patients with ABC in the deidentified Flatiron Health-Foundation Medicine clinico-genomic database (FH-FMI CGDB). Results: PIK3CAm were detected in 11,767/33,977 (35%) of tissue biopsies, including 2,300 (7%) samples with OTHERm and no SOLAR1m. Liquid biopsy had 77% sensitivity detecting PIK3CAm, increasing to 95% with circulating tumor DNA fraction ≥2%. In patients with HR+/HER2− ABC and PIK3CAm receiving alpelisib/fulvestrant (ALP+FUL; n = 182) or fulvestrant alone (FUL; n = 119), median real-world progression-free survival (rwPFS) was 5.9 months on ALP+FUL [95% confidence interval (CI): 5.1–7.4] versus 3.1 months on FUL (95% CI: 2.7–3.7; P &amp;lt; 0.0001). In patients with OTHERm, median rwPFS was 4.0 months on ALP+FUL (95% CI: 2.8–10.1) versus 2.5 months on FUL (95% CI: 2.2–3.7; P = 0.0054). Conclusions: CGP detects diverse PIK3CAm in a greater number of patients with ABC than PCR hotspot testing; 20% of patients with PIK3CAm do not have SOLAR1m. These patients may derive benefit from alpelisib. See related commentary by Tau and Miller, p. 989
Pathogenesis of Cardiomyopathy Caused by Variants in <i>ALPK3</i> , an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere
Authors: Radhika Agarwal, Hiroko Wakimoto, Joao A. Paulo, Qi Zhang, Daniel Reichart, Christopher Toepfer, Arun Sharma, Angela C. Tai, Mingyue Lun, Joshua Gorham, Steven R. DePalma, Steven P. Gygi, J.G. Seidman, Christine E. Seidman
Journal: Circulation (2022)

ALPK3 encodes α-kinase 3, a muscle-specific protein of unknown function. ALPK3 loss-of-function variants cause cardiomyopathy with distinctive clinical manifestations in both children and adults, but the molecular functions of ALPK3 remain poorly understood.We explored the putative kinase activity of ALPK3 and the consequences of damaging variants using isogenic human induced pluripotent stem cell-derived cardiomyocytes, mice, and human patient tissues.Multiple sequence alignment of all human α-kinase domains and their orthologs revealed 4 conserved residues that were variant only in ALPK3, demonstrating evolutionary divergence of the ALPK3 α-kinase domain sequence. Phosphoproteomic evaluation of both ALPK3 kinase domain inhibition and overexpression failed to detect significant changes in catalytic activity, establishing ALPK3 as a pseudokinase. Investigations into alternative functions revealed that ALPK3 colocalized with myomesin proteins (MYOM1, MYOM2) at both the nuclear envelope and the sarcomere M-band. ALPK3 loss-of-function variants caused myomesin proteins to mislocalize and also dysregulated several additional M-band proteins involved in sarcomere protein turnover, which ultimately impaired cardiomyocyte structure and function.ALPK3 is an essential cardiac pseudokinase that inserts in the nuclear envelope and the sarcomere M-band. Loss of ALPK3 causes mislocalization of myomesins, critical force-buffering proteins in cardiomyocytes, and also dysregulates M-band proteins necessary for sarcomere protein turnover. We conclude that ALPK3 cardiomyopathy induces ventricular dilatation caused by insufficient myomesin-mediated force buffering and hypertrophy by impairment of sarcomere proteostasis.
Substrate Ablation by Multivein, Multiballoon Coronary Venous Ethanol for Refractory Ventricular Tachycardia in Structural Heart Disease
Authors: Miguel Valderrábano, Stephanie C. Fuentes Rojas, Adi Lador, Apoor Patel, Paul A. Schurmann, Carlos Tapias, Diego Rodríguez, Luis Carlos Sáenz, Maan Malahfji, Dipan J. Shah, Nilesh Mathuria, Amish S. Dave
Journal: Circulation (2022)

Ablation of ventricular tachycardia (VT) in the setting of structural heart disease often requires extensive substrate elimination that is not always achievable by endocardial radiofrequency ablation. Epicardial ablation is not always feasible. Case reports suggest that venous ethanol ablation (VEA) through a multiballoon, multivein approach can lead to effective substrate ablation, but large data sets are lacking.VEA was performed in 44 consecutive patients with ablation-refractory VT (ischemic, n=21; sarcoid, n=3; Chagas, n=2; idiopathic, n=18). Targeted veins were selected by mapping coronary veins on the epicardial aspect of endocardial scar (identified by bipolar voltage <1.5 mV), using venography and signal recording with a 2F octapolar catheter or by guidewire unipolar signals. Epicardial mapping was performed in 15 patients. Vein segments in the epicardial aspect of VT substrates were treated with double-balloon VEA by blocking flow with 1 balloon while injecting ethanol through the lumen of the second balloon, forcing (and restricting) ethanol between balloons. Multiple balloon deployments and multiple veins were used as needed. In 22 patients, late gadolinium enhancement cardiac magnetic resonance imaged the VEA scar and its evolution.Median ethanol delivered was 8.75 (interquartile range, 4.5-13) mL. Injected veins included interventricular vein (6), diagonal (5), septal (12), lateral (16), posterolateral (7), and middle cardiac vein (8), covering the entire range of left ventricular locations. Multiple veins were targeted in 14 patients. Ablated areas were visualized intraprocedurally as increased echogenicity on intracardiac echocardiography and incorporated into 3-dimensional maps. After VEA, vein and epicardial ablation maps showed elimination of abnormal electrograms of the VT substrate. Intracardiac echocardiography demonstrated increased intramural echogenicity at the targeted region of the 3-dimensional maps. At 1 year of follow-up, median of 314 (interquartile range, 198-453) days of follow-up, VT recurrence occurred in 7 patients, for a success of 84.1%.Multiballoon, multivein intramural ablation by VEA can provide effective substrate ablation in patients with ablation-refractory VT in the setting of structural heart disease over a broad range of left ventricular locations.
Different Gene Sets Are Associated With Azacitidine Response In Vitro Versus in Myelodysplastic Syndrome Patients
Authors: Marguerite-Marie Le Pannérer, Jeannine Diesch, Raquel Casquero, Michael Maher, Olga Garcia, Torsten Haferlach, Johannes Zuber, Andrea Kündgen, Katharina S. Götze, Marcus Buschbeck
Journal: HemaSphere (2022)

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by dysplasia, ineffective hematopoiesis, and predisposition to secondary acute myeloid leukemias (sAML). Azacitidine (AZA) is the standard care for high-risk MDS patients not eligible for allogenic bone marrow transplantation. However, only half of the patients respond to AZA and eventually all patients relapse. Response-predicting biomarkers and combinatorial drugs targets enhancing therapy response and its duration are needed. Here, we have taken a dual approach. First, we have evaluated genes encoding chromatin regulators for their capacity to modulate AZA response. We were able to validate several genes, whose genetic inhibition affected the cellular AZA response, including 4 genes encoding components of Imitation SWItch chromatin remodeling complex pointing toward a specific function and co-vulnerability. Second, we have used a classical cohort analysis approach measuring the expression of a gene panel in bone marrow samples from 36 MDS patients subsequently receiving AZA. The gene panel included the identified AZA modulators, genes known to be involved in AZA metabolism and previously identified candidate modulators. In addition to confirming a number of previously made observations, we were able to identify several new associations, such as NSUN3 that correlated with increased overall survival. Taken together, we have identified a number of genes associated with AZA response in vitro and in patients. These groups of genes are largely nonoverlapping suggesting that different gene sets need to be exploited for the development of combinatorial drug targets and response-predicting biomarkers.
The <i>FES</i> Gene at the 15q26 Coronary-Artery-Disease Locus Inhibits Atherosclerosis
Authors: Elisavet Karamanavi, David G. McVey, Sander W. van der Laan, Paulina J. Stanczyk, Gavin E. Morris, Yifan Wang, Wei Yang, Kenneth Chan, Robin N. Poston, Jun Luo, Xinmiao Zhou, Peng Gong, Peter D. Jones, Junjun Cao, Renata B. Kostogrys, Tom R. Webb, Gerard Pasterkamp, Haojie Yu, Qingzhong Xiao, Peter A. Greer, Emma J. Stringer, Nilesh J. Samani, Shu Ye
Journal: Circulation Research (2022)

Background: Genome-wide association studies have discovered a link between genetic variants on human chromosome 15q26.1 and increased coronary artery disease (CAD) susceptibility; however, the underlying pathobiological mechanism is unclear. This genetic locus contains the FES (FES proto-oncogene, tyrosine kinase) gene encoding a cytoplasmic protein-tyrosine kinase involved in the regulation of cell behavior. We investigated the effect of the 15q26.1 variants on FES expression and whether FES plays a role in atherosclerosis. Methods and Results: Analyses of isogenic monocytic cell lines generated by CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing showed that monocytes with an engineered 15q26.1 CAD risk genotype had reduced FES expression. Small-interfering-RNA-mediated knockdown of FES promoted migration of monocytes and vascular smooth muscle cells. A phosphoproteomics analysis showed that FES knockdown altered phosphorylation of a number of proteins known to regulate cell migration. Single-cell RNA-sequencing revealed that in human atherosclerotic plaques, cells that expressed FES were predominately monocytes/macrophages, although several other cell types including smooth muscle cells also expressed FES . There was an association between the 15q26.1 CAD risk genotype and greater numbers of monocytes/macrophage in human atherosclerotic plaques. An animal model study demonstrated that Fes knockout increased atherosclerotic plaque size and within-plaque content of monocytes/macrophages and smooth muscle cells, in apolipoprotein E-deficient mice fed a high fat diet. Conclusions: We provide substantial evidence that the CAD risk variants at the 15q26.1 locus reduce FES expression in monocytes and that FES depletion results in larger atherosclerotic plaques with more monocytes/macrophages and smooth muscle cells. This study is the first demonstration that FES plays a protective role against atherosclerosis and suggests that enhancing FES activity could be a potentially novel therapeutic approach for CAD intervention.
Supramolecular Polypeptide Self‐Assembly Mediated In Situ Elicitation of Robust Innate and Adaptive Immune Responses Boosts Immunogenic Photothermal Therapy toward “Cold” Tumor
Authors: Kai Shi, Xiu Liu, Yuli Liu, Chang Liu, Yaxin Wang, Yunmeng Liu
Journal: Advanced Healthcare Materials (2022)

As a promising cancer treatment modality that has emerged, photothermal therapy can harness antitumor immunity by triggering immunogenic cell death (ICD) in addition to direct cell ablation. However, the immuno-stimulation induced by PTT alone is insufficient to achieve satisfactory cancer eradication, especially in immunologically "cold" tumors due to their harsh immunosuppressive microenvironment. Effective activation of the innate immune system is indispensable to boost a robust adaptive antitumor immune response typically initiated by dendritic cells (DCs). Herein the above issues are addressed by constructing an environmentally responsive supramolecular nanoself-assembly (PSAs) derived from a novel polypeptide-based block copolymer, which is capable of co-load photothermal immunomodulators efficiently under structure-guided π-π stacking interactions. In the murine model of 4T1 xenograft tumors, the fabricated PSAs with payloads trigger both adaptive and innate immune responses in situ through activation of ICD as well as STING-dependent signal pathway. The findings reveal a new mechanism of harnessing photothermal therapy toward immunologically "cold" tumors.
Transmission dynamics of monkeypox in the United Kingdom: contact tracing study
Authors: Thomas Ward, Rachel Christie, Robert S Paton, Fergus Cumming, Christopher E Overton
Journal: BMJ (2022)

To analyse the transmission dynamics of the monkeypox outbreak in the UK, declared a Public Health Emergency of International Concern in July 2022.Contact tracing study, linking data on case-contact pairs and on probable exposure dates.Case questionnaires from the UK Health Security Agency (UKHSA), United Kingdom.2746 people with polymerase chain reaction confirmed monkeypox virus in the UK between 6 May and 1 August 2022.The incubation period and serial interval of a monkeypox infection using two bayesian time delay models-one corrected for interval censoring (ICC-interval censoring corrected) and one corrected for interval censoring, right truncation, and epidemic phase bias (ICRTC-interval censoring right truncation corrected). Growth rates of cases by reporting date, when monkeypox virus was confirmed and reported to UKHSA, were estimated using generalised additive models.The mean age of participants was 37.8 years and 95% reported being gay, bisexual, and other men who have sex with men (1160 out of 1213 reporting). The mean incubation period was estimated to be 7.6 days (95% credible interval 6.5 to 9.9) using the ICC model and 7.8 days (6.6 to 9.2) using the ICRTC model. The estimated mean serial interval was 8.0 days (95% credible interval 6.5 to 9.8) using the ICC model and 9.5 days (7.4 to 12.3) using the ICRTC model. Although the mean serial interval was longer than the incubation period for both models, short serial intervals were more common than short incubation periods, with the 25th centile and the median of the serial interval shorter than the incubation period. For the ICC and ICRTC models, the corresponding estimates ranged from 1.8 days (95% credible interval 1.5 to 1.8) to 1.6 days (1.4 to 1.6) shorter at the 25th centile and 1.6 days (1.5 to 1.7) to 0.8 days (0.3 to 1.2) shorter at the median. 10 out of 13 linked patients had documented pre-symptomatic transmission. Doubling times of cases declined from 9.07 days (95% confidence interval 12.63 to 7.08) on the 6 May, when the first case of monkeypox was reported in the UK, to a halving time of 29 days (95% confidence interval 38.02 to 23.44) on 1 August.Analysis of the instantaneous growth rate of monkeypox incidence indicates that the epidemic peaked in the UK as of 9 July and then started to decline. Short serial intervals were more common than short incubation periods suggesting considerable pre-symptomatic transmission, which was validated through linked patient level records. For patients who could be linked through personally identifiable data, four days was the maximum time that transmission was detected before symptoms manifested. An isolation period of 16 to 23 days would be required to detect 95% of people with a potential infection. The 95th centile of the serial interval was between 23 and 41 days, suggesting long infectious periods.
The dynamics of monkeypox transmission
Authors: Esther E Freeman, Sam Abbott, Brett Kurpiel, Tochi Okwor
Journal: BMJ (2022)

After a surge of monkeypox infections starting in May 2022, with more than 70 000 cases globally-including 99% from countries without previous known endemic spread-by the end of August 2022, new infections started to trend downward. 1 2Whether this marks the end of the outbreak or whether intermittent surges will continue is not yet clear.Understanding the underlying transmission dynamics is key to shedding light on this, as well as informing future interventions.
Accurate prediction of histological grading of intraductal papillary mucinous neoplasia using deep learning
Authors: Dominik Schulz, Markus Heilmaier, Veit Phillip, Matthias Treiber, Ulrich Mayr, Tobias Lahmer, Julius Mueller, Ihsan Ekin Demir, Helmut Friess, Maximilian Reichert, Roland M. Schmid, Mohamed Abdelhafez
Journal: Endoscopy (2022)

Background Risk stratification and recommendation for surgery for intraductal papillary mucinous neoplasm (IPMN) are currently based on consensus guidelines. Risk stratification from presurgery histology is only potentially decisive owing to the low sensitivity of fine-needle aspiration. In this study, we developed and validated a deep learning-based method to distinguish between IPMN with low grade dysplasia and IPMN with high grade dysplasia/invasive carcinoma using endoscopic ultrasound (EUS) images. Methods For model training, we acquired a total of 3355 EUS images from 43 patients who underwent pancreatectomy from March 2015 to August 2021. All patients had histologically proven IPMN. We used transfer learning to fine-tune a convolutional neural network and to classify “low grade IPMN” from “high grade IPMN/invasive carcinoma.” Our test set consisted of 1823 images from 27 patients, recruiting 11 patients retrospectively, 7 patients prospectively, and 9 patients externally. We compared our results with the prediction based on international consensus guidelines. Results Our approach could classify low grade from high grade/invasive carcinoma in the test set with an accuracy of 99.6 % (95 %CI 99.5 %–99.9 %). Our deep learning model achieved superior accuracy in prediction of the histological outcome compared with any individual guideline, which have accuracies between 51.8 % (95 %CI 31.9 %–71.3 %) and 70.4 % (95 %CI 49.8–86.2). Conclusion This pilot study demonstrated that deep learning in IPMN-EUS images can predict the histological outcome with high accuracy.
Core-shell nanosystems designed for effective oral delivery of polypeptide drugs
Authors: Chao Li, Liwen Yuan, Xuehua Zhang, Aoxue Zhang, Yuanhu Pan, Yulian Wang, Wei Qu, Haihong Hao, Samah Attia Algharib, Dongmei Chen, Shuyu Xie
Journal: Journal of Controlled Release (2022)
Ancestral library identifies conserved reprogrammable liver motif on AAV capsid
Authors: Eric Zinn, Carmen Unzu, Pauline F. Schmit, Heikki T. Turunen, Nerea Zabaleta, Julio Sanmiguel, Allegra Fieldsend, Urja Bhatt, Cheikh Diop, Erin Merkel, Rakesh Gurrala, Bryan Peacker, Christopher Rios, Kathleen Messemer, Jennifer Santos, Reynette Estelien, Eva Andres-Mateos, Amy J. Wagers, Christopher Tipper, Luk H. Vandenberghe
Journal: Cell Reports Medicine (2022)

Gene therapy is emerging as a modality in 21st-century medicine. Adeno-associated viral (AAV) gene transfer is a leading technology to achieve efficient and durable expression of a therapeutic transgene. However, the structural complexity of the capsid has constrained efforts to engineer the particle toward improved clinical safety and efficacy. Here, we generate a curated library of barcoded AAVs with mutations across a variety of functionally relevant motifs. We then screen this library in vitro and in vivo in mice and nonhuman primates, enabling a broad, multiparametric assessment of every vector within the library. Among the results, we note a single residue that modulates liver transduction across all interrogated models while preserving transduction in heart and skeletal muscles. Moreover, we find that this mutation can be grafted into AAV9 and leads to profound liver detargeting while retaining muscle transduction-a finding potentially relevant to preventing hepatoxicities seen in clinical studies.
Pilot study for the treatment of cutaneous neurofibromas in neurofibromatosis type 1 patients using topical sirolimus gel
Authors: Mari Wataya-Kaneda, Yoshiyuki Watanabe, Ayumi Nakamura, Kouji Yamamoto, Kiyoshi Okada, Shinichiro Maeda, Keisuke Nimura, Kotaro Saga, Ichiro Katayama
Journal: Journal of the American Academy of Dermatology (2022)
Surgically targeted radiation therapy (STaRT) trials for brain neoplasms: A comprehensive review
Authors: Yazmin Odia, Alonso N Gutierrez, Rupesh Kotecha
Journal: Neuro-Oncology (2022)

The mainstays of radiation therapy include external beam radiation therapy (EBRT) and internally implanted radiation, or brachytherapy (BT), all with distinct benefits and risks in terms of local or distant tumor control and normal brain toxicities, respectively. GammaTile® Surgically Targeted Radiation Therapy (STaRT) attempts to limit the drawbacks of other BT paradigms via a permanently implanted, bioresorbable, conformable, collagen tile containing four uniform intensity radiation sources, thus preventing deleterious direct contact with the brain and optimizing interseed spacing to homogenous radiation exposure. The safety and feasibility of GammaTile® STaRT therapy was established by multiple clinical trials encompassing the spectrum of primary and secondary brain neoplasms, both recurrent and newly-diagnosed. Implantable GT tiles were FDA approved in 2018 for use in recurrent intracranial neoplasms, expanded to newly-diagnosed malignant intracranial neoplasms by 2020. The current spectrum of trials focuses on better defining the relative efficacy and safety of non-GT standard-of-care radiation strategies for intracranial brain neoplasm. We summarize the key design and eligibility criteria for open and future trials of GT therapy, including registries and randomized trials for newly-diagnosed and recurrent brain metastases as well as recurrent and newly-diagnosed glioblastoma in combination with approved therapies.